Animal Models Research Articles

Proteomimetic polymer blocks mitochondrial damage, rescues Huntington's neurons, and slows onset of neuropathology in vivo.

Recently, it has been shown that blocking the binding of valosin-containing protein (VCP) to mutant huntingtin (mtHtt) can prevent neuronal mitochondrial autophagy in Huntington's disease (HD) models. Herein, we describe the development and efficacy of a protein-like polymer (PLP) for inhibiting this interaction in cellular and in vivo models of HD. PLPs exhibit bioactivity in HD mouse striatal cells by successfully inhibiting mitochondrial destruction. PLP is notably resilient to in vitro enzyme, serum, and liver microsome stability assays, which render analogous control oligopeptides ineffective. PLP demonstrates a 2000-fold increase in circulation half-life compared to peptides, exhibiting an elimination half-life of 152 hours. In vivo efficacy studies in HD transgenic mice (R6/2) confirm the superior bioactivity of PLP compared to free peptide through behavioral and neuropathological analyses. PLP functions by preventing pathologic VCP/mtHtt binding in HD animal models; exhibits enhanced efficacy over the parent, free peptide; and implicates the PLP as a platform with potential for translational central nervous system therapeutics.

Sex-dependent differences in hematopoietic stem cell aging and leukemogenic potential.

Sex influences many biological outcomes, but how sex affects hematopoietic stem cell (HSC) aging and hematological disorders is poorly understood. The widespread use of young animal models to study age-related diseases further complicates these matters. Using aged and long-lived BALB/c mouse models, we discovered that aging mice exhibit sex-dependent disparities, mirroring aging humans, in developing myeloid skewing, anemia, and leukemia. These disparities are underlined by sex-differentiated HSC aging characteristics across the population, single-cell, and molecular levels. The HSC population expanded significantly with aging and longevity in males, but this occurred to a much lesser degree in aging females that instead expanded committed progenitors. Aging male HSCs are more susceptible to BCR-ABL1 transformation with faster development of chronic myeloid leukemia (CML) than female HSCs. Additionally, the loss of the aging regulator Sirt1 inhibited CML development in aging male but not female mice. Our results showed for the first time that sex-differentiated HSC aging impacts hematopoiesis, leukemogenesis, and certain gene functions. This discovery provides insights into understanding age-dependent hematological diseases and sex-targeted strategies for the treatment and prevention of certain blood disorders and cancer.

Matrikine stimulation of equine synovial fibroblasts and chondrocytes results in an in vitro osteoarthritis phenotype.

Osteoarthritis (OA) is a debilitating disease that impacts millions of individuals and has limited therapeutic options. A significant hindrance to therapeutic discovery is the lack of in vitro OA models that translate reliably to in vivo preclinical animal models. An alternative to traditional inflammatory cytokine models is the matrikine stimulation model, in which fragments of matrix proteins naturally found in OA tissues and synovial fluid, are used to stimulate cells of the joint. The objective of this study was to determine if matrikine stimulation of equine synovial fibroblasts and chondrocytes with fibronectin fragments (FN7-10) would result in an OA phenotype. We hypothesized that FN7-10 stimulation of equine articular cells would result in an OA phenotype with gene and protein expression changes similar to those previously described for human chondrocytes stimulated with FN7-10. Synovial fibroblasts and chondrocytes isolated from four horses were stimulated in monolayer culture for 6 or 18 h with 1 µM purified recombinant 42 kD FN7-10 in serum-free media. At the conclusion of stimulation, RNA was collected for targeted gene expression analysis and media for targeted protein production analysis. Consistent with our hypothesis, FN7-10 stimulation resulted in significant alterations to many important genes that are involved in OA pathogenesis including increased expression of IL-1β, IL-4, IL-6, CCL2/MCP-1, CCL5/RANTES, CXCL6/GCP-2, MMP-1, MMP-3, and MMP13. The results of this study suggest that the equine matrikine stimulation model of OA may prove useful for in vitro experiments leading up to preclinical trials.

Neurochemical atlas of the rabbit spinal cord.

Complex neurophysiological and morphologic experiments require suitable animal models for investigation. The rabbit is one of the most successful models for studying spinal cord functions owing to its substantial size. However, achieving precise surgical access to specific spinal regions requires a thorough understanding of the spinal cord's cytoarchitectonic structure and its spatial relationship with the vertebrae. The comprehensive anatomo-neurochemical atlases of the spinal cord are invaluable for attaining such insight. While such atlases exist for some rodents and primates, none exist for rabbits. We have developed a spinal cord atlas for rabbits to bridge this gap. Utilizing various neurochemical markers-including antibodies to NeuN, calbindin 28kDa, parvalbumin, choline acetyltransferase, nitric oxide synthase, and non-phosphorylated heavy-chain neurofilaments (SMI-32 antibody)-we present the visualization of diverse spinal neuronal populations, various spinal cord metrics, stereotaxic maps of transverse slices for each spinal segment, and a spatial map detailing the intricate relationship between the spinal cord and the vertebrae across its entire length.

Intravascular delivery of an ultraflexible neural electrode array for recordings of cortical spiking activity

Although intracranial neural electrodes have significantly contributed to both fundamental research and clinical treatment of neurological diseases, their implantation requires invasive surgery to open craniotomies, which can introduce brain damage and disrupt normal brain functions. Recent emergence of endovascular neural devices offers minimally invasive approaches for neural recording and stimulation. However, existing endovascular neural devices are unable to resolve single-unit activity in large animal models or human patients, impeding a broader application as neural interfaces in clinical practice. Here, we present the ultraflexible implantable neural electrode as an intravascular device (uFINE-I) for recording brain activity at single-unit resolution. We successfully implanted uFINE-Is into the sheep occipital lobe by penetrating through the confluence of sinuses and recorded both local field potentials (LFPs) and multi-channel single-unit spiking activity under spontaneous and visually evoked conditions. Imaging and histological analysis revealed minimal tissue damage and immune response. The uFINE-I provides a practical solution for achieving high-resolution neural recording with minimal invasiveness and can be readily transferred to clinical settings for future neural interface applications such as brain-machine interfaces (BMIs) and the treatment of neurological diseases.

Fasudil Alleviates Postoperative Neurocognitive Disorders in Mice by Downregulating the Surface Expression of α5GABAAR in Hippocampus.

Postoperative neurocognitive disorder (PND) refers to the cognitive impairment experienced by patients after surgery. As a target of sevoflurane, a kind of inhalation anesthetic, the balance of the GABAergic system can be disrupted during the perioperative period. In this study, we explored the promoting effect of abnormal elevation of the α5 subtype of γ-aminobutyric acid type A (GABAA) receptors caused by sevoflurane and surgical trauma on PND, as well as the therapeutic effect of fasudil on PND. Eight-week-old mice were pretreated with fasudil, and after 10 days, sevoflurane-induced femoral fracture surgery was performed to establish an animal model of PND. The Morris water maze and fear conditioning tests were used to evaluate PND induced by this model. Biochemical and electrophysiological analyses were conducted to assess the protective effect of fasudil on the GABAergic system. Following artificial fracture, the hippocampus-dependent memory was damaged in these mice. Fasudil pretreatment, however, ameliorated cognitive function impairment in mice induced by sevoflurane and surgery. Mechanistically, fasudil was found to restore the increased hippocampus expression and function of α5GABAARs in mice with PND. In addition, pretreatment with Fasudil inhibited the enhancement in the calcium ion concentration and phosphorylation of Camk2, as well as the activation of the Radixin pathway which led to increased phosphorylation of the ERM family in the hippocampal CA1 region of the PND model. Preadministration of fasudil improved postoperative cognitive function in PND mice by inhibiting the activation of Camk2 and Radixin pathways and finally downregulating the surface expression of α5GABAAR in hippocampus neurons.

Repercussion of Primary Nucleation Pathway: Dementia and Cognitive Impairment.

Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and prion disease, are characterized by the conversion of normally soluble proteins or peptides into aggregated amyloidal fibrils. These diseases result in the permanent loss of specific types of neurons, making them incurable and devastating. Research on animal models of memory problems mentioned in this article contributes to our knowledge of brain health and functionality. Neurodegenerative disorders, which often lead to cognitive impairment and dementia, are becoming more prevalent as global life expectancy increases. These diseases cause severe neurological impairment and neuronal death, making them highly debilitating. Exploring and understanding these complex diseases offer significant insights into the fundamental processes essential for maintaining brain health. Exploring the intricate mechanisms underlying neurodegenerative diseases not only holds promise for potential treatments but also enhances our understanding of fundamental brain health and functionality. By unraveling the complexities of these disorders, researchers can pave the way for advancements in diagnosis, treatment, and ultimately, improving the lives of individuals affected by neurodegenerative diseases.

Heart failure with preserved ejection fraction in pigs causes shifts in posttranscriptional checkpoints.

Left ventricular pressure overload (LVPO) can lead to heart failure with a preserved ejection fraction (HFpEF) and LV chamber stiffness (LV Kc) is a hallmark. This project tested the hypothesis that the development of HFpEF due to an LVPO stimulus will alter posttranscriptional regulation, specifically microRNAs (miRs). LVPO was induced in pigs (n = 9) by sequential ascending aortic cuff and age- and weight-matched pigs (n = 6) served as controls. LV function was measured by echocardiography and LV Kc by speckle tracking. LV myocardial miRs were quantified using an 84-miR array. Treadmill testing and natriuretic peptide-A (NPPA) mRNA levels in controls and LVPO were performed (n = 10, n = 9, respectively). LV samples from LVPO and controls (n = 6, respectively) were subjected to RNA sequencing. LV mass and Kc increased by over 40% with LVPO (P < 0.05). A total of 30 miRs shifted with LVPO of which 11 miRs correlated to LV Kc (P < 0.05) that mapped to functional domains relevant to Kc such as fibrosis and calcium handling. LVPO resulted in reduced exercise tolerance (oxygen saturation, respiratory effort) and NPPA mRNA levels increased by fourfold (P < 0.05). RNA analysis identified several genes that mapped to specific miRs that were altered with LVPO. In conclusion, a specific set of miRs are changed in a large animal model consistent with the HFpEF phenotype, were related to LV stiffness properties, and several miRs mapped to molecular pathways that may hold relevance in terms of prognosis and therapeutic targets.NEW & NOTEWORTHY Heart failure with preserved ejection fraction (HFpEF) is an ever-growing cause for the HF burden. HFpEF is particularly difficult to treat as the mechanisms responsible for this specific form of HF are poorly understood. Using a relevant large animal model, this study uncovered a unique molecular signature with the development of HFpEF that regulates specific biological pathways relevant to the progression of this ever-growing cause of HF.

Establishing Benchmarks for Airway Replacement: Long-Term Outcomes of Tracheal Autografts in a Large Animal Model.

Airway replacement is a challenging surgical intervention and remains an unmet clinical need. Due to the risk of airway stenosis, anastomotic separation, poor vascularization, and necrosis, it is necessary to establish the gold-standard outcomes of tracheal replacement. In this study, we use a large animal autograft model to assess long-term outcomes following tracheal replacement. Four New Zealand White rabbits underwent tracheal autograft surgery and were observed for 6 months. Clinical and radiographic surveillance were recorded, and grafts were analyzed histologically and radiographically at endpoint. All animals survived to the endpoint with minimal respiratory symptoms and normal growth rates. No complications were observed. Computed tomography scans of the post-surgical airway demonstrated graft patency at all time points. Histological sections showed no sign of stenosis or necrosis with preservation of the native structure of the trachea. We established benchmarks for airway replacement. Our findings suggest that a rabbit model of tracheal autograft with direct reimplantation is feasible and does not result in graft stenosis or airway collapse.

Investigation of the Efficacy of Nowarta110 in the Treatment of HPV-16 and HPV-18 Oncogenically-transformed Human Cells and Cancer-implanted Animal Models.

Cervical cancer is the third leading cause of cancer-related death in women worldwide. Nearly all cases of cervical cancer are due to infection with human papillomavirus (HPV). Nowata110 has shown breakthrough therapeutic efficacy in phase II clinical study against plantar warts, with no reported side effects. This study evaluated the effectiveness of Nowarta110 in killing cultured HPV-transformed cancer cells and its anti-cancer effects in mice, using both vaginally engrafted and subcutaneously implanted animal cancer models. Nowata110 is a novel compound composed of colloidal silver and fig extract. The cytotoxic properties of Nowarta110 were evaluated on HPV-16 and HPV-18-transformed human cancer cells (ARPE-19/HPV-16 and HeLa cells, respectively). The therapeutic potential of Nowarta110 in vivo was evaluated following the engraftment of ME-180 epidermoid carcinoma cells in the mouse vagina or their subcutaneous implantation. Nowarta110 treatment was initiated when the tumor reached an approximate volume of 65 mm3 Results: Our data showed that HPV16-expressing human retinal pigmented epithelial cells are susceptible to Nowarta110-induced cell death, with a reduction in cell viability observed at 1% Nowarta110 and a complete absence of viable cells at 5% Nowarta110. In HPV18-expressing HeLa cells, Nowarta110 caused significant and rapid cell death at a dose of 5%, whereas lower doses of 1% did not produce the same effects. The results from animal studies indicated that Nowarta110 effectively induced tumor regression in both the intravaginal and subcutaneous tumor models. Nowarta110 effectively induced cell death in HPV-16 and HPV-18-transformed human cancer cells. It also effectively induced tumor regression in mouse models with intravaginally engrafted or subcutaneously implanted cancer cells. Considering the high prevalence of HPV-induced cervical dysplasia and cancer and the lack of treatment, clinical studies to promote the implementation of Nowarta110 are warranted.

PM2.5 Induces Developmental Neurotoxicity in Cortical Organoids

There is mounting evidence implicating the potential neurotoxic effects of PM2.5 during brain development, as it has been observed to traverse both the placental barrier and the fetal blood-brain barrier. However, the current utilization of 2D cell culture and animal models falls short in providing an accurate representation of human brain development. Consequently, the precise mechanisms underlying PM2.5-induced developmental neurotoxicity in humans remain obscure. To address this research gap, we constructed three-dimensional (3D) cortical organoids that faithfully recapitulate the initial stages of human cerebral cortex development. Our goal is to investigate the mechanisms of PM2.5-induced neurotoxicity using 3D brain organoids that express cortical layer proteins. Our findings demonstrate that exposure to PM2.5 concentrations of 5 μg/mL and 50 μg/mL induces neuronal apoptosis and disrupts normal neural differentiation, thereby suggesting a detrimental impact on neurodevelopment. Furthermore, transcriptomic analysis revealed PM2.5 exposure induced aberrations in mitochondrial complex I functionality, which is reminiscent of Parkinson's syndrome, potentially mediated by misguided axon guidance and compromised synaptic maintenance. This study is a pioneering assessment of the neurotoxicity of PM2.5 pollution on human brain tissues based on 3D cortical organoids, and the results are of great significance in guiding the formulation of the next air pollution prevention and control policies in China to achieve the sustainable improvement of air quality and to formulate pollution abatement strategies that can maximize the benefits to public health.

Identification of candidate genes and genomic prediction for early heifer pregnancy in Nelore beef cattle

This study aimed to assess the influence of differential weighting in genomic regions harboring candidate causal loci on the prediction accuracy and inflation for early heifer pregnancy (heifers that calved up to 30 months of age) in Nellore (Bos indicus) heifers using the single step genomic BLUP model (ssGBLUP). Phenotypic records of 102,294 Nellore heifers born between 2010 and 2017 were used in this study. The pedigree dataset harbored information from 176,107 animals born between 1998 and 2017, including 5,145 sires and 35,705 dams. Seven different models for genomic prediction were defined by combining the SNP weights obtained in the iterations (1st and 2nd) of the weighted single step GWAS (ssw1GBLUP and ssw2GBLUP) or candidate QTLs reported in the literature. Hence, the lambda (λ) values estimated in the WssGWAS were used to weight the SNPs adjacent to the candidate regions or QTL previously reported in the literature. To estimate the genetic parameters and perform the WssGWAS and WssGBLUP for early heifer pregnancy, a single-trait Bayesian analysis considering a threshold animal model was used. Accuracy, bias, and inflation parameters were evaluated in the validation subset based on the linear regression (LR) method. Genomic windows of ten consecutive SNPs that explained more than 0.5% of the additive genetic variance were selected to explore and determine possible candidate genes. Among the identified genes, we can highlight the PGRMC2, TENM3, GRIP1, TMEM45A, and KLF3, given their roles in endocrine fertility, expression of contractile proteins, average daily gain, dry matter intake, and fat deposition. Several genomic regions associated with QTL related to early heifer pregnancy were identified. The identification of such regions and the respective candidate genes associated with sexual precocity and fertility would contribute to improve the genetic knowledge regarding early sexual precocity of Nellore cattle. The prediction accuracy increased roughly 25.6% using the ssGBLUP compared to BLUP models. The prediction accuracy with the WssGBLUP when incorporating weighted SNPs with the λ values obtained in the 1st (ssw1GBLUP) and 2nd iteration (ssw2GBLUP) of the WssGWAS was higher (∼18%) than that described for the ssGBLUP model. The inflation also increased the weighting of the most relevant SNPs obtained with the GWAS, most likely overestimating the GEBV. The models that weighted SNPs close to QTLs reported in the literature yielded to less biased and deflated predictions compared to ssw1GBLUP and ssw2GBLUP models. Genomic selection is a feasible alternative for genomic evaluation of early heifer pregnancy in Nellore beef cattle by increasing the prediction accuracy of young animals. In addition, the use of information obtained from the WssGWAS is an alternative to increase reliability and reduce genomic prediction bias. Therefore, the results obtained herein indicate that it is possible to improve the prediction accuracy and reduce the bias of genomic prediction by using genomic information and differentially weighted genomic regions harboring candidate QTLs previously reported in the literature for early heifer pregnancy.

Preliminary evidence that Bunyamwera virus causes severe disease characterized by systemic vascular and multiorgan necrosis in an immunocompromised mouse model.

Bunyamwera virus (BUNV) is the prototypical member of the Bunyamwera serogroup within the Orthobunyvirus genus. BUNV is transmitted by mosquito vectors of the genera Culex, Aedes and Anopheles and has historically circulated in East Africa, though the transmission has been observed in Argentina. BUNV has been identified as an agent of human and animal disease and has also been misdiagnosed as other agents. BUNV is often thought to be an agent of mild febrile illness in humans, though it can cause abortions in ruminants and neurological disease in horses. Joint pain and gastritis have also been attributed to BUNV. There are limited data concerning the possible spectrum of disease and extent of pathogenesis of BUNV infection, and there are currently no therapeutics or vaccines available. Furthermore, options for animal models for Orthobunyaviruses in general - of which BUNV is the prototypical member - are limited. Eight mice deficient in the type I interferon response were infected with BUNV, and all developed overt disease. All mice developed detectable viraemia and clinical signs, including weight loss, hunched posture and lethargy. Three of the eight mice developed severe diseases, including vascular necrosis and necrosis in the liver, lungs, reproductive organs, bone marrow and spleen, as well as haemorrhages (n=1) and severe diffuse facial oedema (n=3), reminiscent of the pathology of Schmallenberg and the Arenaviruses Lassa and Lujo viruses. Thus, BUNV infection of IRF3/7 DKO mice could serve as a BSL-2 model for severe diseases of higher-risk group viruses, which often must be studied at BSL-4. Additionally, our results suggest that BUNV may have the ability to cause severe disease in immunocompromised hosts. Thus, further investigation into the potential spectrum of pathogenesis due to BUNV is important to prioritize for outbreak response, diagnostics and the development of countermeasures.

Enhancement sensitivity of TRPV1 in dorsal root ganglia via the SP-NK-1 pathway contributes to increased bladder organ sensitivity caused by prostatitis

Chronic prostatitis/chronic pelvic pain syndrome is a prevalent condition affecting the male urinary system. The urinary dysfunction resulting from this disorder has a direct or indirect impact on the patient’s quality of life. Recent studies have suggested that organ cross-sensitization between the prostate and bladder may elucidate this phenomenon; however, the specific molecular mechanisms remain unclear. In this study, we simulated the urinary symptoms of prostatitis patients using an animal model and examined the expression of relevant proteins within the prostate-bladder sensitized neural pathway. We found that transient receptor potential vanilloid 1 (TRPV1) protein is highly expressed in the dorsal root ganglia (DRG) that co-innervate both the prostate and bladder, potentially increasing the sensitivity of TRPV1 channels via the substance P-neurokinin 1 (SP-NK-1) pathway, which may exacerbate micturition symptoms. Furthermore, in the absence of bladder inflammation, elevated levels of neurogenic substances in bladder tissue were found to sensitize bladder sensory afferents. Collectively, these results underscore the significant role of TRPV1 in bladder sensitization associated with prostatitis, suggesting that the inhibition of TRPV1 along this sensitization pathway could be a promising approach to treating urinary dysfunction linked to prostatitis in the future.

Mitochondrial Reactive Oxygen Species Dysregulation in Heart Failure with Preserved Ejection Fraction: A Fraction of the Whole

Heart failure with preserved ejection fraction (HFpEF) is a multifarious syndrome, accounting for over half of heart failure (HF) patients receiving clinical treatment. The prevalence of HFpEF is rapidly increasing in the coming decades as the global population ages. It is becoming clearer that HFpEF has a lot of different causes, which makes it challenging to find effective treatments. Currently, there are no proven treatments for people with deteriorating HF or HFpEF. Although the pathophysiologic foundations of HFpEF are complex, excessive reactive oxygen species (ROS) generation and increased oxidative stress caused by mitochondrial dysfunction seem to play a critical role in the pathogenesis of HFpEF. Emerging evidence from animal models and human myocardial tissues from failed hearts shows that mitochondrial aberrations cause a marked increase in mitochondrial ROS (mtROS) production and oxidative stress. Furthermore, studies have reported that common HF medications like beta blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists indirectly reduce the production of mtROS. Despite the harmful effects of ROS on cardiac remodeling, maintaining mitochondrial homeostasis and cardiac functions requires small amounts of ROS. In this review, we will provide an overview and discussion of the recent findings on mtROS production, its threshold for imbalance, and the subsequent dysfunction that leads to related cardiac and systemic phenotypes in the context of HFpEF. We will also focus on newly discovered cellular and molecular mechanisms underlying ROS dysregulation, current therapeutic options, and future perspectives for treating HFpEF by targeting mtROS and the associated signal molecules.

Honey Enriched with Additives Alleviates Behavioral, Oxidative Stress, and Brain Alterations Induced by Heavy Metals and Imidacloprid in Zebrafish

Environmental concerns have consistently been a focal point for the scientific community. Pollution is a critical ecological issue that poses significant threats to human health and agricultural production. Contamination with heavy metals and pesticides is a considerable concern, a threat to the environment, and warrants special attention. In this study, we investigated the significant issues arising from sub-chronic exposure to imidacloprid (IMI), mercury (Hg), and cadmium (Cd), either alone or in combination, using zebrafish (Danio rerio) as an animal model. Additionally, we assessed the potential protective effects of polyfloral honey enriched with natural ingredients, also called honey formulation (HF), against the combined sub-chronic toxic effects of the three contaminants. The effects of IMI (0.5 mg·L−1), Hg (15 μg·L−1), and Cd (5 μg·L−1), both individually and in combination with HF (500 mg·L−1), on zebrafish were evaluated by quantifying acetylcholinesterase (AChE) activity, lipid peroxidation (MDA), various antioxidant enzyme activities like superoxide dismutase and glutathione peroxidase (SOD and GPx), 2D locomotor activity, social behavior, histological and immunohistochemical factors, and changes in body element concentrations. Our findings revealed that all concentrations of pollutants may disrupt social behavior, diminish swimming performances (measured by total distance traveled, inactivity, and swimming speed), and elevate oxidative stress (OS) biomarkers of SOD, GPx, and MDA in zebrafish over the 21-day administration period. Fish exposed to IMI and Hg + Cd + IMI displayed severe lesions and increased GFAP (Glial fibrillary acidic protein) and S100B (S100 calcium-binding protein B) protein expression in the optic tectum and cerebellum, conclusively indicating astrocyte activation and neurotoxic effects. Furthermore, PCNA (Proliferating cell nuclear antigen) staining revealed reduced cell proliferation in the IMI-exposed group, contrasting with intensified proliferation in the Hg + Cd group. The nervous system exhibited significant damage across all studied concentrations, confirming the observed behavioral changes. Moreover, HF supplementation significantly mitigated the toxicity induced by contaminants and reduced OS. Therefore, the exposure to chemical mixtures offers a more complete picture of adverse impacts on aquatic ecosystems and the supplementation with bioactive compounds can help to reduce the toxicity induced by exposure to environmental pollutants.

Cottontail Rabbit Papillomavirus (CRPV) Related Animal Models for Head and Neck Cancer Research: A Comprehensive Review of the Literature

Having suitable animal models is crucial to mimic human disease states and for the successful transfer of experimental data into clinical practice. In the field of papillomavirus research, the domestic rabbit (Oryctolagus cuniculus) has served as an indispensable model organism for almost 100 years. The identification and characterization of the first papillomaviruses in rabbits, their carcinogenic potential and their immunogenicity have contributed significantly to the state of knowledge on the genetics and life cycle of papillomaviruses in general, as well as the development of antiviral strategies such as vaccination procedures. Due to the high species specificity of papillomaviruses, only rabbit papillomaviruses (RPVs) can be used for animal studies on papilloma-based tumor diseases in the rabbit. The major focus of this article is on cottontail rabbit papillomavirus (CRPV)-related rabbit squamous cell carcinoma (RSCC). A brief history outlines the discovery and generation of experimentally used RSCC tumors. A comprehensive overview of the current CRPV-associated VX2 carcinoma-based tumor models with a major focus on human head and neck squamous cell carcinoma (HNSCC) tumor models is provided, and their strengths in terms of transferability to human HNSCC are discussed.

Diagnostic Value of Serum Clara Cell Secretory Protein Level in an Experimental Blunt Chest Trauma Model

Objective: Blunt chest trauma is a significant clinical problem leading to injury of the lungs that may be fatal. Experimental blunt chest trauma is well established in animal models. This study aimed to investigate whether Clara cell secretory protein (CC16) can be a biomarker in an experimentally created blunt chest trauma model. Material and Methods: A total of 30 rabbits were used in our study. A modified bilateral blunt thoracic trauma model was used to produce different levels of lung contusion. We divided the rabbits into four groups according to the energy level at which blunt thoracic trauma was applied. Blood samples were taken from the control and trauma groups to evaluate CC16 levels at 0, 12, and 24 hours. Results: The CC16 levels measured at the start of the experiment were significantly lower in the control and low-energy groups compared to the medium- and high-energy groups (p =.002). While there was a significant difference in CC16 levels measured at the 12th hour (p =.004), no significant difference was found among the groups at the 24th hour. Upon analyzing the change in CC16 levels over time within the groups, we observed that CC16 levels decreased from 0–12 hours and subsequently increased after the 12th hour. Histopathologically, we observed that the level of contusion increased in proportion to the severity of trauma across the different groups. Conclusion: With the designed platform, we created a reproducible experimental model of pulmonary contusion from blunt thoracic trauma in rabbits. Increased levels of CC16 following a lung contusion could serve as a foundation for clinical decision-making. Thus, CC16 has the potential to serve as a rapid and simple biochemical indicator for acute traumatic lung injury.

Diet as a treatment for chronic kidney disease

The management of chronic kidney disease (CKD) includes nutritional interventions aimed at slowing disease progression and mitigating complications. This review examines various dietary approaches for CKD treatment, focusing on carbohydrate intake modulation, ketogenic diets, and plant-based diets. Standard guidelines recommend carbohydrate intake within 45% to 65% of total calories, but there is growing interest in reducing carbohydrate consumption to preserve kidney function. Low-carbohydrate diets (&lt;25% of total calories) have shown benefits in glycemic control and weight reduction but may pose long-term adherence challenges. High-protein, low-carbohydrate diets are discouraged due to associations with hyperfiltration and CKD progression. Limiting fructose intake has been linked to reductions in blood pressure and uric acid levels. Intermittent fasting and ketogenic diets, which promote ketone body production and reduce inflammation, have shown promise in animal models and some human studies, particularly in autosomal dominant polycystic kidney disease, though more research is needed. Plantbased diets, such as the Mediterranean and DASH (Dietary Approaches to Stop Hypertension) diets, offer cardiovascular benefits and may reduce CKD risk but require careful management of potassium intake. Overall, dietary interventions should be individualized, considering potential risks like hyperkalemia and ensuring nutritional adequacy.

A New Augmentation Strategy against Depression Combining SSRIs and the N-terminal Fragment of Galanin (1-15).

Depression is one of the most disabling mental disorders, with the second highest social burden; its prevalence has grown by more than 27% in recent years, affecting 246 million in 2021. Despite the wide range of antidepressants available, more than 50% of patients show treatment-resistant depression. In this review, we summarized the progress in developing a new augmentation strategy based on combining the N-terminal fragment of Galanin (1-15) and SSRI-type antidepressants in animal models.